Faculté de Pharmacie, Université de Montréal, Succursale Centre-Ville, C.P. 6128, Montréal, Québec, H3C 3J7, Canada.
Certara Consulting Services, Montréal, Québec, Canada.
Drugs Aging. 2019 Aug;36(8):747-758. doi: 10.1007/s40266-019-00681-w.
Age-related changes in the concentration-effect relationship of (+)-O-desmethyl-tramadol [(+)-ODM], tramadol's active metabolite, are not documented in the elderly.
The objective of this study was to characterize, in elderly and young subjects, the (+)-ODM pharmacokinetic and pharmacodynamic relationship to examine the effect of age after single-dose administration of tramadol 200 mg extended-release tablets.
A population analysis of a double-blind, randomized, placebo-controlled, two-period cross-over study including 13 elderly (aged ≥75 years) subjects with mild renal insufficiency and 16 young (aged 18-40 years) subjects was conducted. For 48 h post-dose, blood samples were collected and pain tolerance thresholds measured using an electrically stimulated pain model. A pharmacokinetic/pharmacodynamic model incorporating a one-compartment pharmacokinetic model for (+)-ODM parameterized with first-order formation rate, clearance (CL/f), volume of distribution (V/f) and a sigmoid maximum effect (E) model incorporating baseline (E) and placebo effect was used.
Maximum plasma concentrations of (+)-ODM occurred later and plasma concentrations declined more slowly in the elderly than in young subjects. In the elderly, V/f was 76% larger and CL/f 16% slower. Baseline (E) and sensitivity (C) for pain tolerance were similar between young and elderly subjects. However, the E parameter was 2.5 times higher in the elderly and maximum possible treatment-related effect was 169 (135-221) in the young and 194 (149-252) in the elderly; that is, 15% higher in the elderly.
This exploratory analysis suggests that age-related differences exist in the distribution and elimination of (+)-ODM, including a 76% larger distribution outside the central compartment and 16% slower clearance of (+)-ODM. These pharmacokinetic changes are associated with a 15% higher maximum possible treatment-related effect and carry the potential for greater efficacy but also the potential for increased side effects at the same dose in elderly subjects. Clinicaltrials.gov identifier: NCT02329561.
（+）-O-去甲曲马多（（+）-ODM）是曲马多的活性代谢物，其浓度-效应关系随年龄变化的情况在老年人中尚未有相关记录。
本研究旨在描述老年和年轻受试者中（+）-ODM 的药代动力学和药效学关系，以检查单次给予曲马多 200mg 缓释片后年龄的影响。
对一项双盲、随机、安慰剂对照、两周期交叉研究进行群体分析，该研究纳入了 13 名患有轻度肾功能不全的老年（≥75 岁）受试者和 16 名年轻（18-40 岁）受试者。给药后 48 小时内，采集血样并使用电刺激疼痛模型测量疼痛耐受阈值。采用药代动力学/药效学模型，该模型包含一个（+）-ODM 的单室药代动力学模型，参数为一级形成速率、清除率（CL/f）、分布容积（V/f）和一个包含基线（E）和安慰剂效应的 S 型最大效应（E）模型。
（+）-ODM 的最大血浆浓度在老年受试者中出现较晚，且血浆浓度下降较年轻受试者更缓慢。在老年受试者中，V/f 增大 76%，CL/f 减慢 16%。年轻和老年受试者的疼痛耐受基线（E）和敏感度（C）相似。然而，老年受试者的 E 参数高 2.5 倍，最大可能的治疗相关效应在年轻受试者中为 194（149-252），在老年受试者中为 169（135-221），即老年受试者高 15%。
这项探索性分析表明，（+）-ODM 的分布和消除存在与年龄相关的差异，包括中央隔室外分布容积增大 76%和（+）-ODM 清除率减慢 16%。这些药代动力学变化与最大可能的治疗相关效应增加 15%相关，在相同剂量下老年受试者可能具有更高的疗效，但也可能增加副作用的风险。临床试验注册号：NCT02329561。
